Abstract
18β-Glycyrrhetinic acid (GA) is the active ingredient of the traditional Chinese medicine, Glycyrrhrzae Radix et Rhizoma. Here, we explored the effects of GA on hepatocellular carcinoma (HCC) in vitro and in vivo and the underlying molecular mechanisms. We confirmed that GA suppressed proliferation of various HCC cell lines. Treatment of GA caused G0/G1 arrest, apoptosis and autophagy in HCC cells. GA-induced apoptosis and autophagy were mainly due to the unfolded protein response. We compared the roles of the ATF4/CHOP and IRE1α/XBP1s UPR pathways, which were both induced by GA. The ATF4/CHOP cascade induced autophagy and was indispensable for the induction of apoptosis in GA-treated HCC cells. In contrast, the IRE1α/XBP1s cascade protected HCC cells from apoptosis in vitro and in vivo induced by GA. Despite this, activation of autophagy protected HCC cells from apoptosis induced by GA. We concluded that pharmacological inhibition of autophagy or IRE1α may be of benefit to enhance the antitumor activity of GA.
Highlights
Hepatocellular carcinoma (HCC) is the sixth most common malignant tumor, and the third leading cause of cancer mortality worldwide
glycyrrhetinic acid (GA) is the active ingredient of the traditional Chinese medicine, Glycyrrhrzae Radix et Rhizoma, which has been used as hepatoprotective drugs in China and Japan[4]
Numerous studies have confirmed that GA has antitumor effects in breast cancer, non-small-cell lung cancer, and pituitary adenoma by triggering apoptosis, inhibiting proliferation, or suppressing metastasis[7,18,30]
Summary
Hepatocellular carcinoma (HCC) is the sixth most common malignant tumor, and the third leading cause of cancer mortality worldwide. We investigated the role of UPR proteins in mediating the effects of GA in HCC cell lines in vitro and in vivo. To investigate further the effect of GA-induced autophagy on apoptosis, we studied whether GA elicited autophagy in HCC cells. Treatment with CQ significantly increased GA-induced apoptosis in HepG2 and HLF cells (Fig. 4a–d).
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